MHC Class I Antigens of Infected Nucleated Cells Play a Major Role in Activating Cytotoxic T Cells
Cytotoxic killing of intracellularly infected, cancer, or auto- reactive cells is an essential step in survival by containing infected cells or the spread of deleterious cells. For example, a viral infection of any cell in the body yields to viral replication within the cell, and some of these viral peptides will physically bind to intracellular MHC class I antigens (Figure 55-2).
This viral peptide-MHC class 1 complex is carried to the surface and displayed as an altered MHC class 1 molecule. TCR molecules of effector CD8+ cytotoxic T cells will recognize the class I molecule-peptide complex to initiate cytotoxicity by at least four different, but complementary, mechanisms. First, contact of a cytotoxic CD84 cell with an infected cell that is displaying a MHC class I-peptide complex will immediately result in cytoplasmic reorganization within the CD8* cell. This includes the alignment of granules and Golgi apparatus at the site of contact. Perforins in the cytotoxic cells polymerize to form tiny injectable tubes referred to as membrane attack complexes (MACs) that “drill” holes into the target cells. Granzymes are passed from the cytotoxic cells into the target cells through these perforin tubes to initiate apoptosis.The other three mechanisms by which CD8* cells induce apoptosis of target cells are (1) the secretion of Iymphotoxin α (tumor necrosis factor alpha, TNF-α), which binds to its specific receptor on the target cells to initiate apoptosis; (2) the interactions of CD95 ligand on T cells with the CD95 “death” receptor on target cells; and (3) secretion of granulysin, an antibacterial peptide found in granules that activates lipiddegrading enzymes (sphingomyelinases). This in turn results in an increase in saponins, including ceramide, which increase apoptosis. Granulysin kills not only infected target cells, but also bacteria, thus containing the infection.